Methyl-phenyl derivatives, preparation method and use

ABSTRACT

The present invention relates to: 
     a) methylbiphenyl derivatives of general formula:                    
     in which R 1  represents OH, C 3 -C 7  alkyl or C 3 -C 7  cycloalkyl, these compounds being in the form of individual isomers or mixtures thereof, 
     b) their preparation by reaction: 
     either of a hydroxylamine salt with an N-substituted o-(p-tolyl)benzaldimine, to give o-(p-tolyl)benzaldoxime 
     or of an N-substituted 2-halobenzaldimine with a p-tolylmagnesium halide in the presence of an inorganic manganese derivative, to give the compounds of formula I in which R 1  represents C 3 -C 7  alkyl or C 3 -C 7  cycloalkyl 
     c) their use for the preparation of o-(p-tolyl)-benzonitrile, which is an intermediate in the synthesis of medicinal products.

This application is a 371 of PCT/FR99/00593 filed Mar. 17, 1999.

The present invention relates in general to a novel methylbiphenylderivative, to a process for its preparation and to its use as asynthetic intermediate.

More specifically, a subject of the invention is o-tolylbenzaldoxime offormula:

this compound being considered in the form of its individual isomers ormixtures thereof.

The oxime derivative of formula I, referred to hereinbelow as OTBO, hasbeen found to be particularly useful as an intermediate product, inparticular for the preparation of o-(p-tolyl)benzonitrile, which isreferred to hereinbelow as OTBN.

The latter compound may itself be widely used as a particularlyadvantageous intermediate, since it is the key intermediate in thesynthesis of many active principles in medicinal products acting inparticular against hypertension via an angiotensin II inhibitorymechanism.

OTBN was disclosed for the first time in patent EP 253 310 and a certainnumber of processes for synthesizing it have recently been proposed.

One of the processes which appears to be the most suitable for preparingOTBN was disclosed in patent EP 566 488. It consists of the reactionbetween an o-halobenzonitrile and a p-tolylmagnesium halide in thepresence of a manganous salt, preferably MnCl₂. However, this methodproduces as a reaction by-product from 6.5% to 10% by weight of4,4′-dimethylbiphenyl, referred to hereinbelow as bis-tolyl, resultingfrom the self-condensation of the p-tolylmagnesium halide.

In the context of the invention, the possibility of preparing OTBN viaone of its potential precursors, in this instanceo-(p-tolyl)benzaldoxime, was investigated with a view to solving theabove problem.

To this end, attempts were made to apply a process similar to that ofpatent EP 253 310 also using p-tolylmagnesium bromide.

However, tests performed starting with 2-chlorobenzaldoxime and 3.5equivalents of p-tolyl-magnesium bromide, the reaction taking place inthe presence of 0.36 equivalent of MnCl₂ in tetrahydrofuran at 90° C.and for 8 hours, did not produce the expected coupling reaction butrather the massive production of bis-tolyl.

The search for a process for preparing OTBN starting, for example, withthe corresponding oxime, which is itself obtained in an advantageousmanner and is free of the drawbacks mentioned above, remains ofunquestionable interest.

It has now been found, surprisingly, that o-(p-tolyl)benzaldoxime can beobtained in excellent yields and with less than 6% bis-tolyl by-productby a coupling reaction using p-tolylmagnesium bromide and, rather than2-chlorobenzaldoxime, an N-substituted 2-halobenzaldimine, so as to forman N-substituted o-(p-tolyl)benzaldimine which can readily be convertedinto the desired oxime.

According to the invention, this oxime of formula I is obtained byreacting a hydroxylamine salt with a benzaldimine derivative of generalformula:

in which R represents a linear or branched C₃-C₇ alkyl group or a C₃-C₇cycloalkyl group, this compound of formula II being considered in theform of individual isomers or a mixture thereof, which gives the desiredcompounds.

This reaction usually takes place at a temperature of between 0° C. and10° C., preferably between 0° C. and 5° C., and in an aprotic solvent.

In the context of the present invention, the expression “aproticsolvent” means a solvent such as an ether, generally an aliphatic oralicyclic ether, for example tetrahydrofuran, methyl tert-butyl ether,dibutyl ether or dioxane, an aliphatic or aromatic hydrocarbon, such asbenzene, toluene or a xylene, or a halogenated hydrocarbon, such asdichloromethane, dichloroethane, chloroform or tetrachloroethane.

However, an ether is preferably used as solvent, for exampletetrahydrofuran.

Moreover, the hydroxylamine salt, such as the hydrochloride or,preferably, the sulphate, is used in a proportion of from 1.5 to 2.5molar equivalents per molar equivalent of benzaldimine derivative offormula II.

According to this method, OTBO can be obtained in yields of about 90% to93% by weight.

The methylbiphenyl derivatives of formula II are novel and, in thisrespect, constitute another subject of the invention, whether they arein the form of individual isomers or a mixture thereof.

Consequently, the invention also relates, as novel intermediateproducts, to the benzaldimine derivatives of formula II in which Rrepresents a linear or branched C₃-C₇ alkyl group or a C₃-C₇ cycloalkylgroup, these benzaldimine derivatives being in the form of individualisomers or mixtures thereof.

Among these compounds of formula II, those in which R represents atert-butyl group or, better still, a cyclohexyl group constitutepreferred compounds.

The compounds of formula II can be prepared by reacting, in the presenceof an inorganic manganese derivative, a benzaldimine derivative ofgeneral formula:

in which R has the same meaning as above and Hal represents a halogenatom such as chlorine or bromine, this compound being in the form ofindividual isomers or mixtures thereof, with a p-tolylmagnesium halide,such as p-tolylmagnesium chloride or bromide, giving the desiredcompounds.

This coupling reaction is generally carried out in a suitable solventand at a temperature of between −10° C. and the reflux temperature,preferably at the reflux temperature of the reaction medium.

The solvent usually envisaged is a compound of ether type such as analiphatic or alicyclic ether, for example tetrahydrofuran, methyltert-butyl ether, dibutyl ether or dioxane.

However, tetrahydrofuran is a preferred solvent.

In addition, the p-tolylmagnesium halide is generally used in excess, inparticular in a proportion of from 1 to 2 molar equivalents per molarequivalent of compound of formula II, usually in a proportion of about1.5 equivalents.

The inorganic manganese derivative is used in the reaction in aproportion of from 0.1 to 0.5 molar equivalent per molar equivalent ofbenzaldimine derivative of formula II, preferably from 0.15 to 0.30molar equivalent.

This derivative is generally a manganese salt or oxide, but moreparticularly a manganous salt or manganous oxide. However, the manganoussalt preferably corresponds to MnCl₂ or MnCl₄Li₂, it being possible forthe latter to be formed in situ by adding two molar equivalents of LiCland one molar equivalent of MnCl₂.

In this way, the compounds of formula II can be obtained in yields of atleast 85% and with less than 6% bis-tolyl derivative.

For example, the preparation of o-(p-tolyl)-N-cyclohexylbenzaldiminestarting with 0.4 mol of 2-chloro-N-cyclohexylbenzaldimine, 0.15 molarequivalent of MnCl₂ and 1.5 molar equivalents of p-tolylmagnesiumchloride in tetrahydrofuran for 1 hour gave, along with an excellentyield of OTBN, only 5.5% bis-tolyl relative to the starting imine.

As regards the benzaldimine derivatives of formula III, these can beprepared by reaction, at a temperature between room temperature and thereflux temperature and in an aprotic solvent, preferably an ether,between a 2-chloro- or 2-bromobenzaldehyde and an amine of generalformula:

R—NH₂  IV

in which R has the same meaning as above, thus giving the desiredcompounds.

Since this reaction proceeds with the formation of water, it may beadvantageous to carry it out in the presence of an agent for dehydratingthe reaction medium, such as anhydrous magnesium sulphate.

As indicated above, the oxime derivative of formula I can be used toprepare OTBN.

Consequently, the invention relates to o-(p-tolyl)benzaldoxime as anintermediate for the final synthesis of OTBN.

Thus, OTBN can be obtained starting with the oxime derivative of formulaI, for example by subjecting it to the action of a dehydrating agent.

The resulting reaction is usually carried out at a temperature ofbetween room temperature and the reflux temperature of the medium, andin an aprotic solvent, preferably an ether such as tetrahydrofuran.

In the context of the invention, the expression “dehydrating agent”means an agent capable of converting the oxime function into a nitrilefunction, such as, for example, formic acid, phosphorus pentoxide,phosphorus oxychloride, pyridine or dicyclohexylcarbodiimide.

In addition, the dehydration reaction usually takes place in an aproticsolvent, preferably and advantageously in an ether such as, for example,tetrahydrofuran, and at a temperature of between room temperature andthe reflux temperature, preferably at the reflux temperature of thereaction medium.

However, this dehydration reaction can be undertaken in the absence ofsolvent, the dehydrating agent itself acting as the solvent. Such is thecase in particular for formic acid, which can be used both asdehydrating agent and as solvent in the context of the invention.

According to the above method, OTBN is obtained in yields of purifiedand crystallized product of greater than 85%, generally of about 90% to95%, starting from OTBO.

The oxime of formula I and the benzaldimine derivatives of formula IIinvolved in the final synthesis of OTBN can be used after isolation fromthe reaction medium in which they are formed.

Advantageously and preferably, however, OTBN is prepared in the samemedium in which OTBO is formed, without the latter being isolated.

Consequently, the invention also relates to the preparation of OTBNstarting with a benzaldimine derivative of formula II: either:

(a) by reacting this imine in an aprotic solvent with a hydroxylaminesalt at a temperature of between 0° C. and 10° C., so as to form,transiently and without isolation, the oxime of formula I, which istreated with a dehydrating agent at a temperature of between roomtemperature and the reflux temperature, giving the desired compound; or:

(b) by reacting this imine with hydroxylamine-O-sulphonic acid(H₂N—O—SO₃H) in a two-phase medium formed from water and from an aproticsolvent and at a temperature of between room temperature and the refluxtemperature, in order to obtain, transiently and without isolation, theoxime of formula I as a mixture with OTBN, this mixture being treatedwith a dehydrating agent at a temperature of between room temperatureand the reflux temperature, giving the desired compound. This method,which usually takes place in an aprotic solvent, first gives a transientmixture of OTBN/OTBO, generally a mixture of 55% to 75% by weight ofOTBN/45% to 25% by weight of OTBO, followed by OTBN itself in an overallyield of greater than 90% and less than 6% of bis-tolyl compound; or:

(c) by hydrolysing this imine, in an aprotic solvent, to giveo-(p-tolyl)benzaldehyde, which is reacted with a hydroxylamine salt at atemperature of between 0° C. and 10° C., which gives, transiently andwithout isolation, the oxime of formula I, which is treated with adehydrating agent at a temperature of between room temperature and thereflux temperature of the medium, giving the desired compound.

According to alternative embodiments, OTBO and thereafter OTBN can beprepared starting with the imine derivatives of formula III withoutisolating the intermediate products formed.

For example, an imine derivative of formula III under consideration isreacted, in an ether such as tetrahydrofuran, with a p-tolylmagnesiumhalide in the presence of an inorganic manganese derivative and,generally, at a temperature of between −10° C. and the refluxtemperature, to form a benzaldimine derivative of formula II, which isthen converted, without isolation from its reaction medium, into OTBO offormula I and then into OTBN according to one of the methods (a), (b)and (c) above.

The non-limiting examples which follow illustrate the invention.

In these examples, the following abbreviations have been used:

GC: gas chromatography

MS: mass spectrum

IR: infrared spectrum

NMR: nuclear magnetic resonance

OTBCI: o-tolyl-N-cyclohexylbenzaldimine

OTBO: o-(p-tolyl)benzaldoxime

OTBA: o-(p-tolyl)benzaldehyde

OTBTBI: o-(p-tolyl)-tert-butylbenzaldimine

t: retention time.

PREPARATIONS A) 2-Chloro-N-cyclohexylbenzaldimine

9.70 g (0.0806 mol; 1.132 equivalents) of anhydrous magnesium sulphateare placed in a 50 ml two-necked round-bottomed flask equipped with amagnetic stirrer and on which is mounted an ascending condenser. Astream of nitrogen is passed through the round-bottomed flask for 10minutes, and 8 ml (10.01 g; 0.0712 mol; 1 equivalent) of2-chlorobenzaldehyde diluted in 20 ml of tetrahydrofuran are then added.

The mixture is maintained at reflux for 10 minutes with stirring (bathtemperature=90° C.). 8.15 ml (7.07 g; 0.0713 mol; 1 equivalent) ofcyclohexylamine are then added dropwise over 5 minutes so as not tobreak the reflux, which is continued for a further 2 hours.

In this way, a 2-chloro-N-cyclohexylbenzaldimine solution is obtainedGC/MS: t (2-chloro-N-cyclohexylbenzaldimine)=9.92 min; m/z (ion, %)=223(M⁺/Cl 37,10); 222 (M⁺−H/Cl 37,10); 221 (M⁺/Cl 35,30); 221 (M⁺−H/Cl35,30)

IR (CCl₄): ν (cm⁻¹): 30,71 (weak, aromatic CH stretching); 2931 and 2856(strong, alkyl CH stretching); 1636 (strong, CN stretching); 1592, 1568,1470, 1450 and 1440 (medium to strong, aromatic CC stretching); 1383,1346 and 1274 (medium to strong, deformation in the aromatic CH plane).

B) 2-Chloro-N-cyclohexylbenzaldimine

11 ml (13.728 g; 0.0977 mol) of 2-chlorobenzaldehyde are diluted in 50ml of toluene followed by the addition, in a single portion, of 12 ml(10.404 g; 0.105 mol; 1.07 equivalents) of cyclohexylamine, which causesan exothermic reaction. The temperature rises from 18° C. to 38° C. Thereaction mixture is then brought to reflux (bath temperature=124° C.).The solution becomes cloudy.

The water formed is removed using a Dean-Stark system and, afterrefluxing for 3 hours, the reaction is then stopped. The reactionmixture is cooled to room temperature and the toluene is evaporated offusing a rotary evaporator, to give 20.22 g of a brownish viscous liquid(0.091 mol, i.e. a yield of 93.3%) which crystallizes slowly.

In this way, 2-chloro-N-cyclohexylbenzaldimine is obtained.

C) 2-Chloro-N-tert-butylbenzaldimine

11 ml (13.728 g; 0.0977 mol) of 2-chlorobenzaldehyde are added, withstirring, to 16 ml (11.136 g; 0.152 mol; 1.56 equivalents) oftert-butylamine in a 50 ml two-necked round-bottomed flask equipped witha magnetic stirrer and an ascending condenser, which gives rise to anexothermic reaction. The temperature rises from 16° C. to 37° C. A redfog then appears in the yellowish solution. 15 ml of toluene are thenadded, which makes the solution turn cloudy.

The final mixture is then maintained at 50° C. for 2 hours, and then at127° C. for 1 hour in Dean-Stark apparatus so as to remove the water,and, after refluxing for 30 minutes, the reaction is stopped.

The solution is cooled to room temperature and the toluene is evaporatedoff on a rotary evaporator.

In this way, 17.99 g (0.092 mol) of 2-chloro-N-tert-butylbenzaldimineare obtained in the form of a yellowish viscous liquid whichcrystallizes slowly.

Yield: 94%

GC/MS: t=5.85 min; m/z (ion, %)=197 (M⁺/Cl 37,1); 196 (M⁺−H/Cl 37,1);195 (M⁺/Cl 35,5); 194 (M⁺−H/Cl 35,5)

IR (CCl₄): ν (cm−¹): 3080, 2940 (weak, aromatic CH stretching); 2970(strong, alkyl CH stretching); 1636 (strong, CN stretching); 1593, 1568,1471 and 1441 (medium to strong, aromatic CC stretching); 1372 to 1274(medium to strong, deformation in the aromatic CH plane).

EXAMPLE 1 o-(p-Tolyl)-N-cyclohexylbenzaldimine

The solution of 1 equivalent of 2-chloro-N-cyclohexylbenzaldimineobtained in Preparation A is filtered under nitrogen into a 250 mlthree-necked round-bottomed flask containing 1.34 g (0.0106 mol; 0.15equivalent) of manganese chloride, and the magnesium sulphate is washedwith 58.85 ml of anhydrous tetrahydrofuran and under nitrogen. Thefiltrate obtained is then added to the above filtrate.

The final suspension thus obtained comprising 0.75 mol of2-chloro-N-cyclohexylbenzaldimine is then maintained at reflux for 10minutes (bath temperature=92° C.) with magnetic stirring, and 1.52equivalents of p-tolylmagnesium chloride are added dropwise thereto atreflux over 30 minutes.

The suspension becomes dark, fleetingly turns green, becomes blood redand then ends up dark brown. After adding the magnesium derivative, themixture is refluxed for 1 hour and a sample is then taken and treatedwith a water/ice mixture and extracted with diethyl ether. The organicphase is then analysed by gas chromatography, which reveals the desiredcompound as well as the presence of bis-tolyl, and traces of p-cresoland possibly of OTBA.

In this way, an o-(p-tolyl)-N-cyclohexylbenzaldimine solution isobtained.

GC/MS: t (OTBCI): 13.47 min; m/z (ion, %)=277 (M⁺, 20); 276 (M⁺−H, 100);194 (M⁺-cyclohexyl, 70).

By following the same process as above, but starting with2-chloro-N-tert-butylbenzaldimine, o-(p-tolyl)-N-tert-butylbenzaldimine(Example 2) was prepared.

GC/MS: t (OTBTBI): 10.87 min; m/z (ion, %)=251 (M⁺, 5); 250 (M⁺−H, 10);236 (M⁺−CH₃, 70); 194 (M⁺-tert-butyl, 100); 179 (M⁺-tert-butyl-CH₃,100).

EXAMPLE 3 o-(p-Tolyl)benzaldoxime

The reaction mixture obtained in Example 1 is cooled to room temperaturewithout stirring, so as to settle out the inorganic species whichprecipitate (brown powder), and it is then added slowly, with stirring,into 150 ml of an ice-cold (0° C. to 5° C.) solution of 23.37 g (0.1424mol; 2 equivalents) of hydroxylamine sulphate.

The two-phase mixture is then stirred vigorously for one hour and isallowed to warm to room temperature.

3 ml (2.65 g; 0.0226 mol; 2 equivalents relative to the manganesechloride) of N,N-diethyl-ethanolamine are then added to the mixture withstirring.

After 10 minutes, the stirring is stopped and the phases are allowed toseparate by settling.

The upper organic phase is recovered and the aqueous phase is extractedwith 3 times 100 ml of dichloromethane (pH of the aqueous phase=4). Thetotal organic phase is dried over magnesium sulphate, filtered and thenevaporated under vacuum using a rotary evaporator, to give 11.00 g ofwhite flakes (overall chemical yield: 73% starting from2-chlorobenzaldehyde, the amount of bis-tolyl by mass in the mixturebeing 4%).

50 ml of petroleum ether (30-40° C. fraction) are added to the solidthus obtained and the mixture is stirred for 15 minutes. The white solidformed is filtered off and rinsed under cold conditions with 10 ml ofpetroleum ether.

In this way, 10.62 g of o-(p-tolyl)benzaldoxime are collected in theform of white flakes no longer containing traces of bis-tolyl.

Crude overall yield: 67.5% starting from 2-chlorobenzaldehyde.

The oxime thus obtained can be recrystallized (dichloromethane/petroleumether) to give white leaflets. Purity: 100%.

GC/MS: t (OTBO): 10.97 min; m/z (ion, %)=211 (M⁺, 25); 210 (M⁺−H, 100);194 (M⁺−OH, 60).

IR (CCl₄): ν (cm⁻¹) : 3596 (strong, free OH stretching, dilutesolution); 3312 (weak, bound OH stretching); 3061, 3026 and 2924 (weak,aromatic CH stretching); 1516, 1480, 1447 and 1397 (weak to medium,aromatic CC stretching); 1260, 1200 and 1112 (weak to medium,deformation in the aromatic CH plane); 952 (strong, NO stretching).

¹H NMR: (CDCl₃) δ(ppm): 2.45 (broad s, 3H, CH₃); 7.28 (broad m, 4H, H8,H9, H11 and H12); 7.43 (broad m, 3H, H4, H5 and CHN); 7.95 (broad m, 1H,H3); 8.22 (broad s, 1H, H2) and 9.27 (broad, 1H, OH).

¹³C NMR: (CDCl₃) δ(ppm): 21.22 (CH₃); 126.20; 127.53; 129.15; 129.59;129.69; 129.84 and 130.37 (aromatic CHs); 136.56; 137.42 and 142.36(aromatic C) and 149.85 (CH═NOH).

EXAMPLE 4 o-(p-Tolyl)benzaldehyde

The solution of 1 equivalent of 2-chloro-N-cyclohexylbenzaldimineobtained in Preparation A is filtered under nitrogen into a 250 mlthree-necked round-bottomed flask containing 1.34 g (0.0106 mol; 0.15equivalent) of manganese chloride, and the procedure as described inExample 1 is continued, in particular by adding 1.52 equivalents ofp-tolylmagnesium chloride.

The reaction is then stopped by introduction into a mixture of 200 ml ofwater/ice and this mixture is extracted with 3 times 100 ml ofdichloromethane after filtration through paper of a very viscous browndeposit. The total organic phase is dried over magnesium sulphate,filtered and then evaporated under vacuum, to give 16.29 9 of a brownishviscous liquid. The liquid obtained is absorbed onto silica and thesolid formed is placed at the top of a column of silica prepared withpetroleum ether (30-40° C. fraction). The column is eluted with thissolvent until all of the bis-tolyl has been collected. 0.79 g (4.34mmol) of a solid in crystalline form is thus recovered. The column isthen eluted with a 5/95 v/v dichloromethane/petroleum ether mixture.

In this way, 10.05 g (51.26 mmol) of o-(p-tolyl)benzaldehyde arecollected in the form of a yellowish viscous liquid.

Yield: 72%

GC/MS: t (OTBA): 8.78 min; m/z (ion, %)=196 (M⁺, 75); 195 (M⁺−H, 50);181 (M⁺−CH₃, 100); 167 (M⁺−CHO, 40).

IR (CCl₄): δ(cm⁻¹): 3066, 3028, 2924, 2848 and 2751 (weak, aromatic CHstretching); 1598, 1517, 1476, 1445 and 1392 (weak to medium, aromaticCC stretching); 1256 and 1194 (weak to medium, deformation in thearomatic CH plane).

¹H NMR: (CDCl₃) δ(ppm): 2.44 (s, 3H, CH₃); 7.26-7.28 (m, 4H, H8, H9, H11and H12); 7.42-7.52 (m, 2H, H4 and H5); 7.59-7.64 (m, 1H, H3); 8.00-b8.05 (m, 1H, H2) and 10.00 (s, 1H, CHO).

¹³C NMR: (CDCl₃) δ(ppm); 21.21 (CH₃); 127.56; 128.95; 129.19; 129.87;130.06; 130.81 and 133.53 (aromatic CHs); 133.80; 134.84; 138.04 and146.01 (aromatic C) and 192.51 (CHO).

EXAMPLE 5 o-(p-Tolyl)benzaldoxime

The 10.05 g of o-(p-tolyl)benzaldehyde obtained in Example 4 aredissolved in 50 ml of tetrahydrofuran at room temperature and an aqueoussolution of 16.83 g (0.1025 mol; 2 equivalents) of hydroxylaminesulphate is then added. The two-phase mixture is stirred vigorously atroom temperature for 1 hour. A gas chromatographic analysis indicatesthe disappearance of the OTBA.

The upper organic phase is recovered and the aqueous phase is extractedwith 3 times 50 ml of dichloromethane (pH of the aqueous phase=1). Theorganic phases are combined, dried over magnesium sulphate, filteredthrough a sinter funnel and evaporated under vacuum.

In this way, 10.07 g (0.0477 mol) of o-(p-tolyl)benzaldoxime areobtained.

Yield: 93%.

EXAMPLE 6 o-(p-Tolyl)benzonitrile

5 ml of formic acid are added to 0.54 g (2.56 mmol) ofo-(p-tolyl)benzaldoxime. The suspension obtained is brought to refluxover 1 hour and maintained at this temperature for a further 1 hour(bath temperature: 126° C.).

The mixture dissolves at an internal temperature of 54° C.

The solution is cooled to room temperature, poured into water andextracted with diethyl ether. The ether phase is washed with 0.5N sodiumhydroxide solution until the washing waters are basic (pH of about 9)and then with water until the washing waters are neutral (pH of about7). The organic phase is dried over magnesium sulphate, filtered andevaporated under vacuum to give 0.45 g (2.33 mmol) of an oil whichhardens over time.

In this way, o-(p-tolyl)benzonitrile is obtained in a yield of 91%.

Purity: >95%.

EXAMPLES 7 TO 9 o-(p-Tolyl)benzonitrile

1 molar equivalent of o-(p-tolyl)-N-cyclohexylbenzaldimine is dissolvedin a 1/1 mixture of tetrahydrofuran/water and X molar equivalents ofaminohydroxysulphonic acid are added. This mixture is maintained at atemperature T for 1 hour, which gives a mixture of OTBO/OTBN. Thismixture is diluted in tetrahydrofuran, 10 molar equivalents ofphosphorus pentoxide are then added and the mixture is allowed to reactfor a further 1 hour at room temperature.

The layer of dehydrating agent turns pink and the OTBO is recovered as amixture with bis-tolyl (<5% by mass). After washing the phosphoruspentoxide layer with tetrahydrofuran, the solvent is evaporated off.

Depending on the starting amounts of aminohydroxysulphonic acid and thereaction temperature used, o-(p-tolyl)benzonitrile is obtained in thefollowing yields:

T Mixture of OTBO/OTBN Ex. X (° C.) (% by weight) Yield of OTBN 7 1.9 2055/45 about 92% 8 2.2 65 55/45 about 92% 9 3.1 90 75/25 about 92%

EXAMPLES 10 TO 12 o-(p-Tolyl)benzonitrile

1 molar equivalent of o-(p-tolyl)benzaldoxime is dissolved in the chosensolvent and the dehydrating agent is added. The medium is maintained ata temperature T for H hours. The medium is optionally filtered and isthen poured into water and extracted with diethyl ether.

The ether phase is washed with 0.5N sodium hydroxide solution and thenwith water until neutral.

The resulting solution is dried over magnesium sulphate, filtered andevaporated under vacuum.

Depending on the solvents, dehydrating agent, temperature and reactiontime used, o-(p-tolyl)benzonitrile is obtained in the following yields:

% of OTBN Dehydrat- T H Purified Ex. ing agent Solvent (° C.) (hour)Crude (crystallized) 10 Phosphorus 20 1 100 92 pent-oxide (10 molarequivalents) 11 DCC* Methylene 20 24 100 86 (molar chloride equivalent)12 DCC THF** 90 4 100 90 (1 molar equivalent) *dicyclohexylcarbodiimide**tetrahydrofuran

What is claimed is:
 1. A methylbiphenyl derivative of general formula:

in which R represents a linear or branched C₃-C₇ alkyl group or a C₃-C₇cycloalkyl group, these compounds being considered in the form of theirindividual isomers or mixtures thereof.
 2. A methylbiphenyl derivativeof formula:

this compound being considered in the form of its individual isomers ormixtures thereof.
 3. A methylbiphenyl derivative according to claim 1wherein R represents cyclohexyl.
 4. A methylbiphenyl derivativeaccording to claim 1 wherein R represents tert-butyl.
 5. A process forpreparing a methyl-biphenyl derivative of formula:

this compound being considered in the form of its individual isomers ormixtures thereof, wherein a hydroxylamine salt is reacted with abenzaldimine derivative according to claim 1 to give the desiredcompound.
 6. A process according to claim 5 wherein the reaction takesplace at a temperature of between 0° C. and 10° C.
 7. A processaccording to claim 5 wherein the reaction is carried out in an aproticsolvent.
 8. A process according to claim 7 wherein the aprotic solventis an aliphatic or alicyclic ether, an aliphatic or aromatic hydrocarbonor a halogenated hydrocarbon.
 9. A process according to claim 8 whereinthe aprotic solvent is tetrahydrofuran, methyl tert-butyl ether, dibutylether or dioxane.
 10. A process for preparing a methylbiphenylderivative of general formula:

in which R represents a linear or branched C₃-C₇ alkyl group or a C₃-C₇cycloalkyl group, these compounds being considered in the form of theirindividual isomers or mixtures thereof wherein a benzaldimine derivativeof general formula:

in which R represents a linear or branched C₃-C₇ alkyl group or a C₃-C₇cycloalkyl group and Hal represents a halogen atom, this compound beingin the form of individual isomers or mixtures thereof, is reacted, inthe presence of an inorganic manganese derivative, with ap-tolylmagnesium halide, to give the desired compounds.
 11. A processaccording to claim 10 wherein the reaction takes place at a temperatureof between −10° C. and the reflux temperature.
 12. A process accordingto claim 10 wherein the reaction takes place in an aliphatic oralicyclic ether.
 13. A process according to claim 12 wherein the etheris tetrahydrofuran, methyl tert-butyl ether, dibutyl ether or dioxane.14. A process according to claim 10 wherein from 1 to 2 molarequivalents of p-tolylmagnesium chloride or bromide are used per molarequivalent of benzaldimine derivative of formula III.
 15. A processaccording to claim 10 wherein the inorganic manganese derivative is amanganese salt or a manganese oxide.
 16. A process according to claim 15wherein the manganese salt is a manganous salt and the manganese oxideis manganous oxide.
 17. A process according to claim 16 wherein, themanganous salt is MnCl₂ or MnCl₄Li₂.
 18. A process according to claim 10wherein the inorganic manganese derivative is used in a proportion offrom 0.1 to 0.5 molar equivalent per molar equivalent of benzaldiminederivative of formula III.
 19. A process for preparingo-(p-tolyl)benzonitrile wherein the methylbiphenyl derivative accordingto claim 2 is subjected to the action of a dehydrating agent.
 20. Aprocess according to claim 19 wherein the reaction produced is carriedout at a temperature of between room temperature and the refluxtemperature of the medium.
 21. A process according to claim 19 whereinthe reaction takes place in an aprotic solvent.
 22. A process accordingto claim 21 wherein the aprotic solvent is an ether.
 23. A processaccording to claim 19 wherein the dehydrating agent is formic acid,phosphorus pentoxide, phosphorus oxychloride, pyridine ordicyclohexylcarbodiimide.
 24. A process for preparingo-(p-tolyl)benzonitrile wherein a benzaldimine derivative of formula IIaccording to claim 1 is converted: either: (a) by reacting this imine inan aprotic solvent with a hydroxylamine salt at a temperature of between0° C. and 10° C., so as to form, transiently and without isolation,o-(p-tolyl)benzaldoxime, which is treated with a dehydrating agent at atemperature of between room temperature and the reflux temperature,giving the desired compound, or: (b) by reacting this imine withhydroxylamine-O-sulphonic acid in a two-phase medium formed from waterand from an aprotic solvent and at a temperature of between roomtemperature and the reflux temperature, in order to obtain, transientlyand without isolation, o-(p-tolyl)-benzaldoxime as a mixture witho-(p-tolyl)-benzonitrile, this mixture being treated with a dehydratingagent at a temperature of between room temperature and the refluxtemperature, giving the desired compound, or: (c) by hydrolysing thisimine, in an aprotic solvent, to give o-(p-tolyl)benzaldehyde, which isreacted with a hydroxylamine salt at a temperature of between 0° C. and10° C., which gives, transiently and without isolation,o-(p-tolyl)benzaldoxime, which is treated with a dehydrating agent at atemperature of between room temperature and the reflux temperature ofthe medium, giving the desired compound.
 25. A process according toclaim 24 wherein the benzaldimine derivative of formula II is obtainedby reaction between a benzaldimine derivative of general formula:

in which R represents a linear or branched C₃-C₇ alkyl group or a C₃-C₇cycloalkyl group, this compound being in the form of individual isomersor mixtures thereof, with a p-tolylmagnesium halide in the presence ofan inorganic manganese derivative, and is then converted withoutisolation from its reaction medium.
 26. A process according to claim 5wherein R is cyclohexyl.
 27. A process according to claim 5 wherein R istert-butyl.
 28. A process according to claim 10 wherein R is cyclohexyl.29. A process according to claim 10 wherein R is tert-butyl.
 30. Aprocess according to claim 20 wherein the reaction takes places in anaprotic solvent.
 31. A process according to claim 30 wherein the aproticsolvent is an ether.